Since the understanding of factor involved in the neuropathogenesis of rabies is far from clear, we plan to undertake an in depth study of the genetics, as well as molecular and immune mechanisms involved in the pathogenesis of this disease. Rabies continues to be a significant public health problem both in the US and abroad. In the US, the persistence of rabies virus in wildlife represents a continuous threat to humans resulting in a large number of post-exposure treatments and a notable financial burden. Moreover, a possible variant of rabies virus, which has its origin in a particular bat species, has evidently emerged as the primary cause of transmission (eg. bites) and therefore may not always be recognized by clinicians. To gain insight into the recent human rabies cases which originated in the US without history of exposure, we will characterize the virus variants identified with these cases and, in addition, survey the prevalence of rabies infection in fatal encephalitis of unknown origin" in humans in the US. Globally, there is a need for economic, safe, and effective vaccines suitable for mass immunization and rabies virus-specific immunoglobulins, which are used in post-exposure prophylaxis. We therefore propose to study new approaches to the immunoprophylaxis of rabies by developing new non- replicating vaccines for oral delivery and by developing immune therapeutics, such as monoclonal antibodies, and immune modulators so that the potentially hazardous immune sera currently employed in post-exposure treatment can be replaced. The foundation of these studies will be experiments on the molecular and immunological mechanisms involved in the neuropathogenesis of rabies virus.